1. Field of the Inventive Subject Matter
The present inventive subject matter relates to novel methods for treating prostatic intraepithelial neoplasia, comprising administration of a composition comprising therapeutically effective amounts of supercritical extracts of rosemary, turmeric, oregano and ginger; and therapeutically effective amounts of hydroalcoholic extracts of holy basil, ginger, turmeric, Scutellaria baicalensis, rosemary, green tea, huzhang, Chinese goldthread, and barberry.
2. Background
Prostatic Intraepithelial Neoplasia. About 200,000 American men are diagnosed with prostate cancer each year, and millions more develop undiagnosed or hidden microscopic cancer. About 80% of men have microscopic prostate cancer by age 80 years, and the autopsy frequency of prostate cancer is remarkably similar in men around the world despite large differences in clinical detection.
Prostatic intraepithelial neoplasia (hereinafter “PIN”) refers to the putative precancerous end of the continuum of cellular proliferations within the lining of prostatic ducts, ductules, and acini. The term prostatic intraepithelial neoplasia has been generally accepted, although terms such as dysplasia, malignant transformation, and intraductal carcinoma have been used to describe the condition. PIN is characterized by cellular proliferations within pre-existing ducts and acini with cytologic changes mimicking cancer, including nuclear and nucleolar enlargement.
Physiological forms of PIN include tufting, micropapillary, cribriform, and flat. Tufting is the most common feature and is present in 97% of all PIN. Most histologic samples contain multiple patterns, and there are no prognostic differences among the various PIN patterns. PIN spreads through the prostatic ducts in 3 patterns similar to prostate cancer. In the first pattern, neoplastic cells replace the normal luminal secretory epithelium, but there is preservation of the basal layer and basement membrane. Foci of PIN may be indistinguishable from ductal spread of carcinoma when viewed by light microscopy. A second pattern is characterized by direct invasion through the ductal or acinar wall with disruption of the basal cell layer. In a third pattern, neoplastic cells invaginate between the basal cell layers, which sometimes has been described as pagetoid spread.
Prostatic intraepithelial neoplasia is generally accepted in the art as a likely pre-invasive stage of prostate adenocarcinoma. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. Most studies suggest that a large majority of patients with PIN will develop carcinoma at some time. Some studies suggest that that about half to about two-thirds of patients diagnosed with PIN will develop carcinoma within only 2–3 years. Thus, there is a great need for an effective treatment for PIN as a means of reducing or preventing the development of prostate cancer.
The incidence and extent of PIN appear to increase with patient age. PIN is associated with progressive abnormalities of phenotype and genotype that are more similar to cancer than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. The only generally utilized method for detection of PIN is biopsy; PIN does not significantly elevate serum PSA concentration or its derivatives, and it is not apparently visible by current imaging techniques. There is no accepted pharmaceutical or surgical standard of practice for treating PIN. Some studies suggest that androgen deprivation therapy decreases the prevalence and extent of PIN in some patients, suggesting that this form of treatment may be one possible method for chemoprevention. However, androgen deprivation therapy has several side effects, discussed in greater detail below, which make it a less than optimal treatment for many men.
PIN is the most significant risk factor for prostate cancer in needle biopsy specimens. Its role as the preinvasive stage of cancer has been confirmed in two separate mouse models (see Alsikafi, et al., High-grade Prostatic Intraepithelial Neoplasia with Adjacent Atypia Is Associated with a Higher Incidence of Cancer on Subsequent Needle Biopsy than High-grade Prostatic Intraepithelial Neoplasia Alone, Urology, 57(2):296–300 (2001); and Amin, et al., Putative Precursor Lesions of Prostatic Adenocarcinoma: Fact or Fiction? Mod. Pathol., 6(4):476–83 (1993)).
PIN coexists with cancer in more than 85% of cases, but retains an intact or fragmented basal cell layer, unlike cancer which lacks a basal cell layer. The clinical importance of recognizing PIN is based on its strong association with prostatic adenocarcinoma, and its identification in biopsy specimens of the prostate warrants further search for concurrent cancer. PIN alone has no apparent influence on serum Prostate Specific Antigen (hereinafter “PSA”) concentration, and PSA levels are not correlated with PIN. If all procedures fail to identify coexistent carcinoma, and lacking a method for treating PIN, close surveillance and follow-up are indicated. Current clinical practices call for follow-up biopsy is suggested at three to six month intervals for two years, and thereafter at twelve-month intervals for life. Biopsies are both expensive and uncomfortable for the subject, and there is thus an unmet need for PIN treatments.
Although there is no accepted pharmaceutical or surgical standard of practice for treating PIN, to the extent they are used at all, current treatments for PIN include androgen deprivation therapy and radiation therapy. Androgen deprivation therapy has several possible complications, including problems with sexual function, osteoporosis, and loss of muscle mass. Radiation therapy has possible complications including loss of appetite, fatigue, skin reactions such as redness and irritation, rectal burning or injury, diarrhea, cystitis, and blood in the urine. Thus, there is a continuing need for alternative treatments for prostate cancer and for improved treatments for prostatic intraepithelial neoplasia.
Cyclooxygenase Inhibitors. Cyclooxygenase is an enzyme-protein complex with a variety of biochemical actions. There are at least three primary COX isoenzymes, COX-1, COX-2, and COX-3. COX-1 is a constitutive enzyme, produced at a reasonably consistent level at all times. It plays an important role in, for example, gastrointestinal protection, kidney function, and the aggregation of blood platelets. COX-2 production is not constant; it varies depending on signals from various biochemical catalysts. For example, in the case of arthritis inflammation and pain, COX-2 responds to tissue damage by oxidizing arachidonic acid, creating prostaglandins which in turn produce local inflammation. COX-3 has been identified relatively recently (Chandrasekharan, et al., PNAS U.S.A., 99(21):13926–31 (2002)). In humans, COX-3 mRNA is expressed most abundantly in the cerebral cortex and heart tissues. COX-3 activity is selectively inhibited by analgesic/antipyretic drugs. It has been suggested that inhibition of COX-3 could represent a mechanism by which these drugs decrease pain and possibly fever.
Prostaglandins play a major role in the inflammatory process and the inhibition of prostaglandin production, especially production of PGG2, PGH2, and PGE2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (hereinafter “NSAIDs”) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process.
NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the cyclooxygenase enzymes. Traditional non-steroidal anti-inflammatory drugs, such as aspirin, work by inhibiting both COX-1 and COX-2. Thus, non-specific NSAIDs can have a damaging effect on the gastrointestinal tract, kidneys, and liver; blocking COX-1 can make the stomach lining more vulnerable, and reduced thromboxane production thins the blood, making gastrointestinal hemorrhage more likely, and may cause inadequate regulation of cellular immune functions and the secretion of various cytokines. The use of high doses of most common NSAID's can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential.
COX-2 is associated with inflammation and provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Thus, researchers have been motivated to develop selective COX-2 inhibitors to reduce inflammation and relieve pain without the gastrointestinal damage brought on by inhibiting COX-1. In addition, the current scientific understanding in the art suggests that COX-2 inhibition may serve an important function in promoting normal cell growth in the colon, pancreas, breast tissue, and other organ systems.
Some compounds which selectively inhibit cyclooxygenase-2 have been described in U.S. Pat. Nos. 5,380,738, 5,344,991, 5,393,790, 5,434,178, 5,474,995, 5,510,368 and WO documents WO96/06840, WO96/03388, WO96/03387, WO96/25405, WO95/15316, WO94/15932, WO94/27980, WO95/00501, WO94/13635, WO94/20480, and WO94/26731.
Drugs such as valdecoxib, celecoxib, and rofecoxib are intended to selectively inhibit COX-2 with minimal effect on COX-1. However, despite the emphasis on COX-2 inhibition, even these drugs appear to have serious long term side effects, such as the breakdown in digestive protective mucus and prevention of normal healing processes. Thus, there is also a continuing need for more specific and non-specific COX-2 inhibitors which avoid the side effects produced by current COX-1 and COX-2 inhibitors.
Natural COX-2 Inhibitors. Several herbs have been found to inhibit the COX-2 enzyme. For example, holy basil has been found to possess significant anti-inflammatory properties and is capable of blocking both the cyclooxygenase and lipoxygenase pathways of arachidonate metabolism. Ursolic acid and oleanolic acid, two of the recognized phytonutrients of holy basil, have been found to have a significant COX-2 inhibitory effect.
Similarly, shogaols and gingerols, pungent components of ginger, have been found to inhibit cyclooxygenase. Eugenol, another active constituent of several medical herbs, has also been found to be a 5-lipoxygenase inhibitor and to possess potent anti-inflammatory and/or anti-rheumatic properties.
Scutellaria baicalensis also has been found to inhibit the COX-2 enzyme. According to the USDA database, green tea contains six constituents having cyclooxygenase-inhibitor activity. According to the Napralert database, green tea contains fifty one constituents having anti-inflammatory activity. The polyphenols in green tea were found to cause a marked reduction in COX-2. Flavan-3-ol derivatives (+)-catechin, also present in green tea, have been reported to be COX-1 and COX-2 inhibitors. In addition, salicylic acid, another constituent of green tea, also has been found to be a COX-2 inhibitor.
Berberine, found in barberry and Chinese goldthread, has also been found to inhibit COX-2 without inhibiting COX-1 activity.
In U.S. Pat. No. 6,387,416, Applicants disclosed the inventive compositions and their use for reducing inflammation. The contents of U.S. Pat. No. 6,387,416 are hereby incorporated by reference in their entirety. Surprisingly, as discussed in greater detail below, it has been determined that the inventive compositions are useful for treating prostatic intraepithelial neoplasia as well.
Methods for Treating Prostatic Intraepithelial Neoplasia. We have found that COX-2 inhibitors are useful for treating some cancers. We have also found that COX-2 inhibitors are useful for treating prostatic intraepithelial neoplasia. Only a very few patents actually disclose the use of selective COX-2 inhibitors for treating cancer, and none disclose the use of specific or non-specific COX-2 inhibitors for treating prostatic intraepithelial neoplasia. The body of patent art related to PIN, relating to non-invasive diagnosis and methods of treatment using compounds which are not COX-2 inhibitors, is exemplified by the following U.S. Patents.
U.S. Pat. No. 5,935,860 to Patierno, et al., discloses a non-surgical method for identifying prostatic intraepithelial neoplasia, based on expression of the uteroglobin protein as a molecular marker for PIN.
U.S. Pat. Nos. 6,265,448, 6,410,043, 6,413,533, 6,413,534, 6,413,535, and 6,632,447 to Steiner, et al., disclose methods for chemoprevention of prostate neoplasias by administering to a subject an effective dose of specific disclosed chemopreventive agents to prevent recurrence of, suppress, or inhibit prostate cancer, benign prostatic hyperplasia, prostate intraepithelial neoplasia, an abnormally high level of circulating prostate specific antibody (PSA).
U.S. Pat. No. 6,477,426 to Fenn, et al., discloses a system and method for safely heating and destroying cancerous and pre-cancerous conditions of the prostate, as well as benign and pre-benign lesions, including PIN, by irradiation of the prostate tissue with coherent or non-coherent phased array energy.
U.S. Pat. No. 6,630,301 to Gocke, et al., discloses detection of specific extracellular nucleic acids associated with neoplastic, pre-malignant, or proliferative disease, including PIN, in plasma or serum fractions of human or animal blood.
According to virtually all available evidence, PIN is a likely precursor of prostatic adenocarcinoma. The clinical importance of treating PIN is based on its strong association with prostatic adenocarcinoma. Based on the limited body of art disclosing the use of COX-2 inhibitors for treating cancer, the lack of any art relating to the use of COX-2 inhibitors for treating prostatic intraepithelial neoplasia, and the need for effective treatments for prostatic intraepithelial neoplasia as prostate cancer precursor in particular, it is apparent that there is a great and immediate need for methods for treating prostatic intraepithelial neoplasia with COX-2 inhibitors. This need is met by the inventive methods and compositions, which treat prostatic intraepithelial neoplasia and ultimately reduce or eliminate the incidence of prostate cancer, without significant short or long term side effects, such as the sexual dysfunction, androgen insufficiency effects, and gastrointestinal effects discussed above.